The mechanism by which certain cyclic AMP (cAMP) analogs exert lethal effects on tumor cells growing in culture and in animal hosts will be analyzed. Cells will be incubated with labelled analog and its metabolic fate will be determined by chromatography of acid-soluble extracts and nuclei acid digests. Cells resistant to the various analogs will be selected and analog metabolism and possible complementation by cell hybridization will be examined with these variants. Analog cross resistance will also be evaluated in resistant cells. Possible effects of analogs on the biosynthesis of purine and pyrimidine nucleotides, proteins, RNA and DNA will be examined in wild type and resistant cells. Efforts will be made to determine at which stage in the cell cycle different analogs exert their effects. Studies will be initiated relative to the ability of cAMP analogs to inhibit the growth of tumors growing in animal hosts. Analogs which are resistant to phosphodiesterase (PDE) attack will be used as well as ones sensitive to hydrolysis to distinguish cAMP-mediated effects from those of metabolites. Previous results have suggested that the lethal action of the cAMP analogs active in vitro occurs only after PDE hydrolysis. The level of cAMP and PDE activity in a variety of tumors will be analyzed to determine whether or not a correlation exists between the cytotoxicity of a given analog towards a tumor and its PDE activity. The ability of the analogs to interact with tumor cell PDE will be assessed in vivo and in vitro. The ability of lethal cAMP analogs to induce TAT plus or minus aPDE inhibitor will be determined relative to their ability to activate protein kinase in vivo. Finally, the selective ability of a specific nucleoside counterpart of one of the lethal analogs to cause a rapid loss of TAT activity will be investigated.